Abstract 2464: Defective NMD promotes aberrant intron retention in clear cell renal cell carcinoma

Abstract Clear cell renal cell carcinoma (ccRCC) is the 8th most common cancer in the United States, constituting 75% of all kidney cancer cases. Clear cell RCC (ccRCC) along with melanoma has traditionally been viewed as an immunotherapy responsive disease with a storied history of immunotherapy treatments including high dose interleukin 2 (IL2), interferon, and allogeneic stem cell transplant. Indeed, RCC was one of the first tumor types to garner FDA approval for PD1 immune checkpoint inhibition (ICI). However, unlike melanoma, most RCC tumors do not have a high tumor mutational burden (TMB) to potentially explain their immunotherapy responsiveness. We and others have sought to explain this unanswered question and have demonstrated that non-canonical tumor associated antigens like endogenous retroviruses (ERVs) may in part explain ICI response in RCC. We have noted that ccRCC tumors have the highest level of retained introns (RI) across all TCGA tumors, that RI levels are secondary to suppressed non-sense mediated decay (NMD) activity, and that one can subset ccRCC into RI-high and normal-like tumors. Moreover, we have found that mTOR signaling plays a key role in regulating NMD and intron retention and that mTOR inhibition can promote intron retention. We hypothesized that these aberrantly retained introns could serve as a rich source of highly foreign, tumor associated neoantigens and that of retained intron neoantigens, the ones not observed in normal tissue would be the most immunogenic. We derived a so called “Neo-RI-antigen burden” that represents the burden of retained intron neoantigens not found in normal tissues and demonstrate that the Neo-RI-antigen burden of complete responders is numerically higher than those with partial response or progressive disease in a dataset of immunotherapy treated melanoma patients. Our work suggests the possibility of using NMD-targeting drugs as a potential therapeutic in combination with ICI to enhance the overall treatment response. Citation Format: Mi Zhou, Gilbert Giri, William Y. Kim, Daniel Dominguez. Defective NMD promotes aberrant intron retention in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2464.